Glomerular diseases are the most common cause of adult chronic and end stage renal diseases in the US. Podocytes, which form the final filtration barrier at the blood-urine interface, are the predominant cell type affected by diabetic nephropathy and other non-diabetic glomerular kidney diseases. Podocyte loss, either by cell death or detachment, is directly related to the progression of glomerular disease. Thus, understanding how podocytes develop and respond to injury is critical for the rational design of therapeutic interventions. Glial cell line-derived neurotrophic factor (GDNF) and its receptor tyrosine kinase, Ret, are upregulated selectively by podocytes in animal models of glomerular disease. GDNF is a potent survival factor for neurons and has been studied intensively because of its therapeutic promise in Parkinson's disease. We demonstrated that podocytes are protected by GDNF during in vitro podocyte injury models. We hypothesize that the GDNF-Ret signaling pathway is critical for the development, maintenance, and recovery of podocytes to injury in vivo. Specifically, I will: (1) test the hypothesis that the GDNF-Ret signaling pathway is required for the development and maintenance of podocytes and glomerular function, (2) test the hypothesis that GDNF functions as an adaptive response to prevent the progression of glomerular diseases in vivo, and that the administration of exogenous GDNF is a therapeutic intervention, and (3) test the hypothesis that Cbl-3 is the E3-ligase controlled by CD2AP that is responsible for Ret degradation and signaling. It is my goal that by understanding the physiologic function of this pathway and its adaptor molecules, novel therapeutic targets for glomerular disease will be identified. This grant will provide the support necessary for me to acquire the basic science training and scientific knowledge necessary to become an independent clinician scientist leading my own research laboratory. My goal is also to develop the skills necessary for independent critical thinking, writing, and the planning of innovative experiments and questions. I am fortunate to have the guidance of my mentor, Dr. Lawrence Holzman, and the collective breadth and depth of knowledge and expertise in podocyte biology from the Nephrology Division at University of Michigan. PUBLIC HEALTH RELEVANCE: Clinical and basic science studies have demonstrated that podocytes are the main target of injury in many adult kidney diseases that progress to chronic and end stage renal diseases. The goal of our proposal is to understand these mechanisms and to discover molecules controlling the growth and health of the podocyte with the intent that this knowledge will facilitate the development of new therapeutic strategies.